Alzheimer’s disease (AD) is the most common form of neurodegenerative disease and the leading cause of dementia among the elderly. The cause and progression of neurodegeneration and cognitive decline are poorly understood. Amyloid-β peptide (Aβ) is the main component of diffuse deposits and dense plaques characteristic of the AD-affected brain.  Accumulation of Aβ occurs decades before the onset of dementia and therefore reducing Aβ burden during the presymptomatic stage of AD is a promising clinical strategy^1,2,3. 

The CD33 gene has been identified as a risk factor for AD susceptibility.  CD33 is a sialic acid-binding immunoglobulin-like lectin that has no known function in the brain. CD33 is a type-I integral membrane protein with the extracellular part of this receptor composed of two immunoglobulin domains: one N-terminal V-set domain, which is the sialic acid binding domain, and one IgC2 domain. The sialic acid binding domain of CD33 appears responsible for suppression of microglial clearance of neurotoxic Aβ.^4,5 

To accelerate the development of this potential therapeutic pathway, we report here the high resolution (1.9 Å) 3D atomic structure of the V-set domain of CD33 and report the preliminary findings of our CD33 inhibitor development studies including the identification of low molecular weight compounds which bind to CD33 and show promise as potential inhibitors of CD33 activity.